Computerized Physician Order Entry (CPOE) analgesia-sedation protocols may improve sedation practice and patients' outcomes. We aimed to evaluate the impact of the introduction of CPOE protocol.This was a prospective, observational cohort study of adult patients receiving mechanical ventilation, requiring intravenous infusion of analgesics and/or sedatives, and expected to stay in the intensive care unit (ICU) ≥24 h. As a quality improvement project, the study had three phases: phase 1, no protocol, July 1st to September 30th, 2010; phase 2, post implementation of CPOE protocol, October 1st to December 31st, 2010; and phase 3, revised (age, kidney and liver function adjusted) CPOE protocol, August 1st to October 31st, 2011. Multivariate analyses were performed to determine the independent predictors of mortality.Two hundred seventy nine patients were included (no protocol = 91, CPOE protocol = 97, revised CPOE protocol = 91). Implementation of CPOE protocol was associated with increase of the average daily dose of fentanyl (3720 ± 3286 vs. 2647 ± 2212 mcg/day; p = 0.009) and decrease of hospital length of stay (40 ± 37 vs. 63 ± 85 days, p = 0.02). The revised CPOE protocol was associated with, compared to the CPOE protocol, a decrease of the average daily dose of fentanyl (2208 ± 2115 vs. 3720 ± 3286 mcg/day, p = 0.0002) and lorazepam (0 ± 0 vs. 0.06 ± 0.26 mg/day, p = 0.04), sedation-related complications during ICU stay (3.3 % vs. 29.9 %, p 70 years or with severe kidney or liver impairment. Both the original CPOE protocol and the revised CPOE protocol were not independent predictors of ICU (adjusted odds ratio [aOR] = 1.85, confidence interval [CI] = 0.90-3.78; p = 0.09; aOR = 0.70, CI = 0.32-1.53, p = 0.37; respectively) or hospital mortality (aOR = 1.12, CI = 0.57-2.21, p = 0.74; aOR = 0.80, CI = 0.40-1.59, p = 0.52; respectively).The implementation of a CPOE analgesia-sedation protocol was not associated with improved sedation practices or patients' outcome but with unpredicted increases of an analgesic dose. However, the revised CPOE protocol (age, kidney and liver function adjusted) was associated with improved sedation practices. This study highlights the importance of carefully evaluating the impact of changes in practice to detect unanticipated outcomes.